Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infants worldwide; and human epidemiological studies have identified age at initial RSV infection as an independent risk factor for the development of childhood asthma. Our laboratory, and others, have used neonatal (i.e. ?7d of age) mouse models of infection to more closely mimic the interaction between RSV and the human infant immune system. With these models, we demonstrated significant differences in the immune response to RSV of neonates compared to adults. For example, neonatal mice mount a Th2-biased response to RSV infection as do human infants. Reinfection of mice initially infected as neonates induces airway inflammation characterized by neutrophils and eosinophils, mucus hyperproduction, and airways hyperreactivity, all symptoms of severe human RSV disease. We previously found that much of these age-dependent responses were mediated by increased levels of IL4R? on neonatal myeloid dendritic cells (mDCs) and Th2 cells and by early signaling by IL13. Here, our preliminary data demonstrate that this early IL13 is induced as a result of increased type II innate lymphoid cells (ILC2s) and the increase in ILC2s is driven by rapidly elevated levels of IL33 in the neonatal RSV-infected lung. This is correlated with defective IL1? production in RSV-infected neonates, which we believe to be responsible for elevated IL33 (i.e. lack of negative regulation of IL33 by IL1? and/or caspase 1 in airway epithelial cells). Although IL33 has been studied extensively in other disease states, no study has investigated the role of IL33 in RSV pathogenesis in a neonatal/infant immune system. Our findings lead to our current, novel hypothesis that inchoate IL1? production by neonatal AECs during RSV infection results in excessive pulmonary IL33 that activates DCs promoting Th2-biased immunopathogenesis. We will explore the validity of this hypothesis using unique sample sets from human infant RSV infection cohorts and age-relevant mouse models through the following specific aims. Aim 1 will demonstrate that neonatal progenitor airway epithelial cells (AECs) orchestrate RSV immunopathogenesis via IL33. We will also demonstrate that IL33 is predictive of RSV disease severity in infants. Aim 2 will determine if age-related differences in IL1? responses by AECs are responsible for increased IL33 levels and the production of more active forms of IL33 in response to neonatal RSV using innovative methodologies for targeted quantitative investigation of IL33 form variants. Aim 3 will identify mechanisms whereby IL33 directly activates pulmonary DCs to prime nave CD4+ T cells to induce Th2-biased responses. The concept of age-dependent regulation of IL33 presented here is novel and will provide molecular mechanisms responsible for the human infant immune response to RSV. In addition, the data derived from these studies are expected to have a positive paradigm- shifting impact in understanding severe RSV disease and should yield novel immunological targets to advance pediatric vaccine design.